The present invention relates to novel compounds, processes for their preparation, and pharmaceutical compositions containing them.
EPA 0733628 discloses a series of indole derivatives which are said to possess 5HT1F agonist activity. These compounds are alleged to be of use in the treatment of migraine and associated disorders. EPA 0533266/7/8 disclose a series of benzanilide derivatives which are said to possess 5-HT1D receptor antagonist activity. The 5-HT1D receptor was subsequently found to consist of a pair of gene products originally designated 5-HT1Dxcex1 and 5-HT1Dxcex2 receptors which have more recently been reclassified as 5-HT1D and 5-HT1B receptors, respectively. (Hartig, P. R. et al., Trends in Pharmacological Sciences 1992, Vol. 13, page 152, Hartig, P. R. et al., Trends in Pharmacological Sciences, 1996, Vol. 17, page 103).
A structurally distinct class of compounds have now been found that are ligands for 5HT1A, 5HT1B and 5HT1D receptors. It is expected that such compounds will be useful for the treatment and prophylaxis of various disorders. In a first aspect, the present invention therefore provides a compound of formula (I) or a salt thereof: 
in which Ra is a group of formula (i) 
in which P1 is phenyl, bicyclic aryl, a 5 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur; R1 is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, COC1-6alkyl, C1-6alkoxy, hydroxy, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkoxy, nitro, trifluoromethyl, cyano, SR9, SOR9, SO2R9, SO2NR10R11, CO2R10, CONR10R11, CONR10(CH2)cCO2R11, (CH2)cNR10R11, (CH2)cCONR10R11, (CH2)cNR10COR11, (CH2)cCO2C1-6alkyl, CO2(CH2)cOR10, NR10R11, NR10CO2R11, NR10CONR10R11, CR10xe2x95x90NOR11 where R9 is C1-6alkyl, R10 and R11 are independently hydrogen or C1-6alkyl and c is 1 to 4;
R2 is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, C1-6alkoxy, COC1-6alkyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R10, CONR10R11, NR10R11 where R10 and R11 are as defined in R1;
a is 1,2 or 3;
or Ra is a group of formula (ii) 
xe2x80x83wherein
p2 and p3 are independently phenyl, bicyclic aryl, a 5- to 7- membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
A is a bond or oxygen, S(O)m where m is 0, 1 or 2, carbonyl, or CH2 or NR4 where R4 is hydrogen or C1-6alkyl;
R1 is as defined above for formula (i) or is a 5 to 7-membered heterocyclic ring, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by C1-6alkyl, halogen or C1-6alkanoyl;
R2 and R3 are as defined for R2 in formula (i);
and a and b are independently 1, 2 or 3;
L is a group of formula
xe2x80x94Yxe2x80x94C(xe2x95x90V)xe2x80x94DGxe2x80x94
xe2x80x83in which
Y is xe2x80x94NHxe2x80x94, NR5 where R5 is C1-6alkyl, or Y is xe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94,
V is oxygen or sulphur;
D is nitrogen, carbon or a CH group, G is hydrogen or C1-6alkyl, providing that D is nitrogen or a CH group, or G together with Rb forms a group W where W is (CR16R17)t where t is 2, 3 or 4 and R16 and R17 are independently hydrogen or C1-6alkyl or W is (CR16R17)uxe2x80x94J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR16xe2x95x90CR17, CR16xe2x95x90N, xe2x95x90CR16O, xe2x95x90CR16S or xe2x95x90CR16xe2x80x94NR17 provided that u is not 0 when J is oxygen or sulphur; subject to the proviso that when D is nitrogen, G is hydrogen or C1-6alkyl, Q is selected such that together with the phenyl ring to which it is attached it forms an indole ring and further that when:
(a) Y is xe2x80x94NHxe2x80x94 or xe2x80x94NR5xe2x80x94 and V is oxygen or sulphur; or
(b) both Y and V are oxygen; or
(c) Y is CH2 and V is oxygen
then p1 is not phenyl within the definition of Ra formula (i) and
Ra is not an unsubstituted biphenyl within the definition of formula (ii)
Q is an optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
RY is a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur;
Rb is hydrogen, halogen, hydroxy, C1-6alkyl, trifluoromethyl, C1-6alkoxy or aryl; or Rb together with G forms a group W as defined above;
C1-6alkyl groups whether alone or as part of another group may be straight chain or branched. The term xe2x80x98acyloxyxe2x80x99 is used herein to describe a group xe2x80x94OC(O)C1-6alkyl. The term xe2x80x98arylxe2x80x99 is used herein to describe, unless otherwise stated, a group such as phenyl. The term xe2x80x98aralkylxe2x80x99 is used herein to describe, unless otherwise stated, a group such as benzyl.
The bicyclic aryl group represented by p1, p2 and/or p3, which may be partially saturated, is preferably naphthyl.
Examples of bicyclic heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur include quinoline, isoquinoline, indole, benzofuran and benzothiophene rings. The heterocyclic groups can be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom.
Examples of 5 to 7 membered heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur represented by p1, p2 and/or p3, include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrimidyl and pyrazinyl, preferably pyridyl.
R1 is preferably a halogen atom for example, fluorine, chlorine or bromine, and R2 and/or R3 are each preferably hydrogen, halogen for example a chloro group or a C1-6alkyl group for example a methyl group.
a and b are each preferably 1 or 2.
Within the definition of Ra formula (ii), A is preferably a bond.
In the group L, as defined above:
Y is preferably xe2x80x94NHxe2x80x94.
V is preferably oxygen.
D is preferably nitrogen and G is preferably a hydrogen atom or together with Rb forms group W, preferably xe2x80x94(CH2)2xe2x80x94.
Rb is preferably hydrogen or Rb together with G forms group W referred to above.
Suitably Q is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur. Preferably Q is a 5- or 6-membered ring containing one or two heteroatoms. Preferably Q, together with the phenyl group to which it attached, forms an indole, indoline, benzoxazole, benzopyran, benzothiophene or benzoxazine ring. Suitable optional substituents for the ring Q include groups R1 and R2 as defined above, preferably C1-6alkyl, most preferably methyl.
The group RY can be fully or partially saturated and can be linked to the group Q via a carbon atom or, when present, a suitable nitrogen atom. Preferably RY is 5 or 6 membered heterocyclic containing 1 or 2 nitrogen atoms. Most preferably RY is a piperidinyl group.
Particularly preferred compounds according to the invention include:
N-[3-(1-Methylpiperidin-4-yl)indol-5-yl]-N-[4-(pyridin-4-yl)naphth-1-yl]-urea,
N-[3-(1-Methylpiperidin-4-yl)indol-5-yl]-Nxe2x80x2-[3-methyl-4-(pyridin-4-yl)phenyl]-urea,
N-[2,3-Dichloro-4-(pyridin-4-yl)phenyl]-Nxe2x80x2-[3-(-methylpiperidin-4-yl)indol-5-yl]-urea,
N-[2-Chloro-4-(pyridin-4-yl)phenyl]-Nxe2x80x2-[3-(1-methylpiperidin-4-yl)indol-5-yl]-urea
N-[3-(1-Methylpiperidin-4-yl)indol-5-yl]-4-(pyridin-4-yl)naphth-1-ylacetamide,
N-[2,3-Dichlorophenyl]-Nxe2x80x2-[7-(1-methylpiperidin-4-yl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indol-1-yl]-urea,
N-[7-(1-Methylpiperidin-4-yl)-1,2,3,5-tetrahydropyrrolo[2,3f]indol-1-yl]-Nxe2x80x2-[4-(pyridin-4-yl)naphth-1-yl]-urea,
N-[3-Chloro-4-(pyridin-4-yl)phenyl]-Nxe2x80x2-[3-(1-methylpiperidin-4-yl)indol-5-yl]-urea,
N-[3-Chloro-4-(pyridin-4-yl)phenyl]-Nxe2x80x2-[3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)benzo[b]thiophen-5-yl]-urea,
N-[3-(1-Methyl-1,2,5,6-tetrahydropyridin-4-yl)benzo[b]thiophen-5-yl]-Nxe2x80x2-[4-(pyridin-4-yl)naphth-1-yl]-urea,
N-[3-Chloro-4-(pyridin-4-yl)phenyl]-Nxe2x80x2-[3-(1-methylpiperidin-4-yl)benzo[b]thiophen-5-yl]-urea,
N-[3-(1-Methylpiperidin-4-yl)benzol[b]thiophen-5-yl]-Nxe2x80x2-[4-(pyridin-4-yl)naphth-1-yl]-urea
or pharmaceutically acceptable salts thereof Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates.
Certain compounds of formula (a) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and the mixtures thereof including racemates.
Compounds of the invention can be prepared using procedures known in the art. In a further aspect the present invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof which comprises:
(a) where D is nitrogen and Y is NH, coupling a compound of formula (II):
Raxe2x80x94Nxe2x95x90C(xe2x95x90V)xe2x80x83xe2x80x83(II)
xe2x80x83in which Ra and V are as defined in formula (I) or a protected derivative thereof with a compound of formula (III). 
xe2x80x83in which Rb, RY, G, and Q are as defined in formula (I), or a protected derivative thereof; or
(b) where D is nitrogen and Y is NH or NR5, reacting a compound of formula (IV)
Ra xe2x80x94NH2 or Ra xe2x80x94NR5Hxe2x80x83xe2x80x83(IV)
xe2x80x83in which Ra and R5 are as defined in formula (I) with a compound of formula (III) together with an appropriate urea forming agent;
(c) where D is nitrogen, reacting a compound of formula (V)
xe2x80x83Ra xe2x80x94Yxe2x80x94(Cxe2x95x90O)xe2x80x94L2xe2x80x83xe2x80x83(V)
in which Ra is as defined in formula (I),
Y is xe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94 and L2 is an appropriate leaving group, with a compound of formula (III)
(d) where D is carbon or CH, reacting a compound of formula (VI)
Raxe2x80x94NH2xe2x80x83xe2x80x83(VI)
xe2x80x83in which Ra is as defined in formula (I) with a compound of formula (VII) 
xe2x80x83in which D is carbon or CH, Rb, RY, G, and Q are as defined in formula (I) and L2 is an appropriate leaving group and optionally thereafter:
removing any protecting groups,
converting a compound of formula (I) into another compound of formula (I),
forming a pharmaceutically acceptable salt.
The reaction in process (a) is conveniently effected in an organic solvent such as dichloromethane.
In process (b) the urea forming agent can be carbonyl demidazole, triphosgene or phosgene, and carried out in an inert organic solvent such as dimethylformamide, tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
In process (c) the leaving group L2 may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
In process (d) the leaving group L2 may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques.
Intermediate compounds of formula (II), (III), (IV), (V), (VI) and (VII) can be prepared using standard procedures known in the art.
It will be appreciated to those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. Standard protection and deprotection techniques can be used. For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. These groups can be removed by conventional procedures well known in the art.
Carboxylic acid groups can be protected as esters. Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection is achieved using standard conditions.
The involvement of serotonin receptors in a number of pharmacological effects has been reviewed by R. A. Glennon in xe2x80x9cSerotonin Receptors: Clinical Implicationsxe2x80x9d, Neuroscience and Behavioural Reviews, 1990, 14, 35 and by L. O. Wilkinson and C. T. Dourish in xe2x80x9cSerotonin Receptor Subtypes: Basic and Clinical Aspectsxe2x80x9d S. Peroutka Ed., John Wiley and Sons, New York, 1991 p.147.
Serotonin (5-hydroxytryptamine; 5HT) receptors have been implicated in a number of pharmacological effects including mood disorders including depression, seasonal affective disorder and dysthymia, anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnesic disorders and age-associated memory impairment; disorders of eating behaviours, including anorexia nervosa and bulimia nervosa, sleep disorders (including disturbances of Circadian rhythm), motor disorders such as Parkinson""s disease, dementia in Parkinson""s disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders. Serotonin receptor ligands have been shown to be of use in the treatment of emesis and nausea and may also be of use in endocrine disorders such as hyperlactinaemia, vasospasm (particularly in the cerebral vasculature), cerebellar ataxia and hypertension, as well as disorders of the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction and hypothermia.
Ligands with high affinity for the 5HT1 receptors are well recognised as having therapeutic utility for the treatment of the above conditions. For example: WO 95/31988 refers to the use of a 5-HT1D receptor antagonist in conjunction with a 5-HT1A receptor antagonist to- treat CNS, endocrine and GI disorders; K. Rasmussen (Annual Reports in Medicinal Chemistry, (1995) 30, 1) describes the utility of 5-HT1A receptor agonists and partial agonists in the treatment of various CNS disorders; P. Trouillas (Progress in Brain Research, C. I. de Zeeuw, P. Stara and J. Voogd, Eds. 1997, 144, 589) and G. Maura (J. Neurochemistry, 1996, 66, 202) propose that administration of agonist ligands selective for the 5-HT1A receptor or for both 5-HT1A and 5-HT1D receptors should provide effective treatment for human cerebellar ataxias.
The present invention also provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of the aforementioned disorders.
In a further aspect the invention provides a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof.
In particular the invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression.
The affinities of the compounds of this invention for the 5HT1A, 5-HT1B and 5-HT1D receptors can be determined by the following radioligand binding assay. HEK 293 cells expressing 5-HT1A receptors (4xc3x97107/ml) are homogenised in Tris buffer and stored in 1 ml aliquots. CHO cells expressing 5-HT1B receptors (4xc3x97107 cells/ml) are homogenised in Tris buffer and stored in 1.5 ml aliquots. CHO cells expressing 5-HT1D receptors (0.563xc3x97108/ml) are homogenised in Tris buffer and stored in 1 ml aliquots. 0.4 ml of a cell suspension is incubated with [3H]-5-HT (4 nM) for 5-HT1B/1D receptors and [3H]-8-OH DPAT (1 nM) for 5-HT1A receptors in Tris Mg HCl buffer (pH 7.7) and test drug, at 37xc2x0 C. for 45 minutes. Each test drug is tested at 10 concentrations (0.01 mM to 0.3 nM final concentration), with non-specific binding defined using 0.01 mM 5-HT. The total assay volume is 0.5 ml. Incubation is stopped by rapid filtration using a Packard Filtermate (filters pre-soaked in 0.3% polyethylenimine) and radioactivity measured by Topcount scintillation counting. pKi values are calculated from the IC50 generated by an iterative least squares curve fitting programme.
The intrinsic activity of the compounds of this invention can be determined according to the following procedure. HEK293 cell membranes stably expressing human 5-HT1A receptors and CHO cell membranes stably expressing human 5-HT1B receptors are homogenised in HEPES/EDTA buffer and stored in 1 ml aliquots, and [35S]GTPxcex3S binding studies are carried out essentially as described by Lazareno et al., (Life Sci., 1993, 52, 449) with some minor modifications. Membranes from 106 cells are pre-incubated at 30xc2x0 C. for 30 minutes in 20 mM HEPES buffer (pH 7.4) in the presence of MgCl2 (3 mM), NaCl (100 mM), GDP (10 xcexcM) and ascorbate (0.2 mM), with or without test compounds. The reaction is started by the addition of 10 xcexcl of [35S]GTPxcex3S (100 pM, assay concentration) followed by a further 30 minutes incubation at 30xc2x0 C. Non-specific binding is determined using nonradiolabelled GTPxcex3S (20 xcexcM) added prior to the membranes. The reaction is terminated by rapid filtration through Whatman GF/B grade filters followed by 5xc3x971 ml washes with ice cold HEPES (20 mM)/MgCl2 (3 mM) buffer. Radioactivity is measured using liquid scintillation spectrometry. This procedure is hereafter referred to as the [35S]GTPxcex3S functional assay.
The compounds of formula (I) show high affinity for the 5HT1A, 5-HT1B and 5-HT1D receptors. It has been found, using the [35S]GTPxcex3S functional assay, that certain compounds of formula (I) appear to be antagonists whilst others appear to be agonists, partial agonists or inverse agonists. The difficulties in describing intrinsic activity of drugs acting at G protein coupled receptors is recognised in the art (Hoyer and Boddeke, Trends in Pharmocological Sciences, July 1993, [Vol. 14], page 270-275). We believe that however these ligands are classified according to this functional assay, the compounds of this invention will be useful antidepressants in vivo.
It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, a selective serotonin reuptake inhibitor (SSRI) antidepressant.
The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.